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Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons
Citation
Liu, JJ and Kim, y and Yan, F and Ding, Q and Ip, V and Jong, NN and Mercer, JFB and McKeage, MJ, Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons, Biochemical Pharmacology, 85, (2) pp. 207-215. ISSN 0006-2952 (2013) [Refereed Article]
Copyright Statement
Copyright 2012 Elsevier Inc
DOI: doi:10.1016/j.bcp.2012.10.023
Abstract
Dorsal root ganglion (DRG) neurons are affected by platinum-induced neurotoxicity and neurodegenerative
processes associated with disturbed copper homeostasis and transport. This study aimed to
understand the role of copper transporter 1 (Ctr1) in the uptake and toxicity of copper and platinum
drugs in cultured rat DRG neurons, and the functional activities of rat Ctr1 (rCtr1) as a membrane
transporter of copper and platinum drugs. Heterologous expression of rCtr1 in HEK293 cells (HEK/rCtr1
cells) increased the uptake and cytotoxicity of copper, oxaliplatin, cisplatin and carboplatin, in
comparison to isogenic vector-transfected control cells. Cultured rat DRG neurons endogenously
expressed rCtr1 protein on their neuronal cell body plasma membranes and cytoplasm, and displayed
substantial capacity for taking up copper, but were resistant to copper toxicity. The uptake of copper by
both cultured rat DRG neurons and HEK/rCtr1 cells was saturable and inhibited by cold temperature,
silver and zinc, consistent with it being mediated by rCtr1. Cultured rat DRG neurons accumulated
platinum during their exposure to oxaliplatin and were sensitive to oxaliplatin cytotoxicity. The
accumulation of platinum by both cultured rat DRG neurons and HEK/rCtr1 cells, during oxaliplatin
exposure, was saturable and temperature dependent, but was inhibited by copper only in HEK/rCtr1
cells. In conclusion, rCtr1 can transport copper and platinum drugs, and sensitizes cells to their
cytotoxicities. DRG neurons display substantial capacity for accumulating copper via a transport process
mediated by rCtr1, but appear able to resist copper toxicity and use alternative mechanisms to take up
oxaliplatin.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | copper transporter 1, copper uptake, platinum anticancer drugs, peripheral neurotoxicity, dorsal root ganglion |
| Research Division: | Medical and Health Sciences |
| Research Group: | Pharmacology and Pharmaceutical Sciences |
| Research Field: | Clinical Pharmacology and Therapeutics |
| Objective Division: | Health |
| Objective Group: | Other Health |
| Objective Field: | Health not elsewhere classified |
| Author: | Liu, JJ (Dr Johnson Liu) |
| ID Code: | 86348 |
| Year Published: | 2013 |
| Web of Science® Times Cited: | 19 |
| Deposited By: | Pharmacy |
| Deposited On: | 2013-09-06 |
| Last Modified: | 2017-12-07 |
| Downloads: | 220 View Download Statistics |
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